Protein Needs of Preterm Infants: Why Are They So Difficult to Meet?

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1 Protein in the Feeding of Preterm Infants Bhatia J, Shamir R, Vandenplas Y (eds): Protein in Neonatal and Infant Nutrition: Recent Updates. Nestlé Nutr Inst Workshop Ser, vol 86, pp , (DOI: / ) Nestec Ltd., Vevey/S. Karger AG., Basel, 2016 Protein Needs of Preterm Infants: Why Are They So Difficult to Meet? Ekhard E. Ziegler Department of Pediatrics, University of Iowa, Iowa City, IA, USA Abstract Because of their exceedingly high rate of growth, premature infants have very high needs for all nutrients. Requirements have been estimated by the factorial method based on the body composition of the fetus. Failure to meet the high requirements for protein impairs growth and places the infant at risk of neurodevelopmental impairments. Human milk, the preferred feeding for premature infants because of its protective effects, does not provide adequate amounts of nutrients and must be fortified. On the basis of studies performed several decades ago using very high protein intakes, in the past it has been believed that protein intakes that met the high needs of premature babies are dangerous for premature babies. To prevent protein intakes from being too high, the protein content of fortifiers in the past has been kept low. Today, this fear of protein is still the reason why protein intakes tend to be kept low, with the result that protein intakes are often too low Nestec Ltd., Vevey/S. Karger AG, Basel Introduction Protein intakes of premature infants are often inadequate. The judgment of inadequacy rests on the fact that growth of a premature infants is less than that of a fetus. It is not based on a comparison between actual intakes and estimates of requirements. Compromised growth provides irrefutable evidence of protein inadequacy. Premature infants must digest and absorb enormous amounts of nutrients compared to any other age group. But the digestion and absorption of protein does not present the infant with any particular problems. So, we need to

2 Table 1. Estimated protein needs for weight gain like the fetus (factorial method, modified from Ziegler [4]) Body weight 500 to 700 g 700 to 900 g 900 to 1,200 g 1,200 to 1,500 g 1,500 to 1,800 g 1,800 to 2,200 g Fetal weight gain per day g g/kg Protein, g/kg per day Loss Growth (accretion) Required intake Parenteral Enteral Protein/energy, g/100 kcal Parenteral Enteral ask: Why do premature infants show evidence of protein deficiency while receiving seemingly adequate amounts of other nutrients? The following discussion will attempt to answer this question. The evidence that protein intakes are inadequate consists in the growth failure that premature infants so often display. For example, Poindexter [1] reports that as many as 80% of premature infants who participated in the NIH research network in showed growth failure. Other examples documenting widespread growth failure include the report by Fenton et al. [2]. Although other factors may play a role in the causation of growth failure, only inadequate intake of protein can bring about growth failure of the extent and with the consistency observed. The amount of protein needed by the premature infant to duplicate fetal growth is reasonably well known. The requirement is obtained by the factorial method. With this method, the amount of protein the baby needs to add each day in order to grow like the fetus is estimated. This fetal accretion is derived from data on fetal body composition that have been used to construct a reference fetus [3]. Accretion is by far the largest component of requirements of the growing infant. However, in order to be able to grow like the fetus (accrete like the fetus), the baby needs to take in somewhat greater amounts to cover inevitable losses. The required intake shown in table 1 for parenterally fed infants represents accretion plus inevitable losses without any margin that would allow for variation of any kind. Enteral requirements are somewhat larger due to larger inevitable intestinal losses. These estimates represent requirements, meaning that if intakes are less, growth like the fetus will not occur. The smallness of the 122Ziegler

3 Table 2. Estimates of nutrient requirements of infants weighing 500 1,000 g per day (modified from Ziegler [4]) Fetal accretion Estimated requirement Calcium, mg Phosphorus, mg Magnesium, mg Sodium, meq Potassium, meq Chloride, meq margin between absolute needs and requirements reflects the stricture imposed by the fear of protein. As will be pointed out, with other nutrients, much larger margins between accretion and requirements are used. Given the evidence that protein intakes of premature infants frequently are inadequate, i.e. do not support growth like the fetus, one question that must be asked is whether the estimates themselves could be faulty, i.e. too low, and that true protein needs could in fact be higher than estimated. The estimates of protein accretion shown in table 1 are derived from body composition data from 22 fetuses selected from about 170 available in the literature using rigid selection criteria [3]. Forbes [5] selected a larger number of fetuses from the literature using different selection criteria. He also applied a different mathematical model to derive accretion rates. In spite of these differences, the protein accretion rates by Forbes [5] and Ziegler et al. [3] are nearly identical, with the greatest discrepancy being a few percentage points between 29 and 34 weeks of gestation (data not shown). Differences between assumed rates of inevitable losses are similarly small and unable to explain the occurrence of growth failure. Given these small differences, it must be concluded that faulty estimates of fetal protein accretion do not explain the frequently observed shortfall between protein needs and intakes. If, on the other hand, estimates of protein needs were faultily low, intakes would of course be exceeding needs and there would be evidence of protein excess, which is not the case. Nutrient requirements of premature infants are large in comparison to those of more mature infants, and the immature gastrointestinal tract often has difficulty digesting and absorbing the large amounts of nutrients required, especially during the early days and weeks of life. But digestion and absorption of protein do not present the infant with any particular problem. Why is it then that premature infants show evidence of protein inadequacy while needs for all other nutrients are seemingly being met? An explanation of this apparent paradox requires that we take a look at how needs for other nutrients are determined. In table 2 estimates of fetal accretion are juxtaposed with accepted estimates of Protein Deficiency in Premature Infants 123

4 required intakes. It is evident that the margin between accretion and required intakes is far larger than for protein (shown in table 1 ). These larger margins are used in order to cover for uncertainties in estimates of accretion as well as variation in nutrient absorption. It is evident that if the same approach were taken for protein, estimates of protein needs would be considerably higher than shown in table 1. Then, why are estimates of protein requirements derived in a manner that is so different from that for other nutrients? The answer lies in the general reluctance among neonatologists to provide protein intakes that might be considered high. What constitutes high protein intakes has not been defined, most likely because it cannot be defined. But a lack of definition has not prevented the fear of protein from lingering. This concern that protein intakes might somehow be too high and cause adverse effects has its origins in a study by Goldman et al. [6] in 1974 that involved premature infants with birth weight less than 1,300 g. Infants who were fed a formula that provided g/kg per day of protein were found to have significantly lower IQs at follow-up than infants fed a lower-protein formula. The fact that the high-protein formula was created by adding casein to the control (low-protein) formula may have been a factor in addition to the high protein concentration per se. Although such high protein intakes cannot be reached with any of today s feeding regimens, the adverse effects of a high protein content in the formula have not been forgotten and the fear of protein lingers and makes neonatologists wish to avoid even the possibility of unduly high protein intakes. The described differences in how required nutrient intakes are derived from fetal accretion explains why intakes of protein so often fall below requirements. If intakes are set exactly at the requirement level, actual intakes are bound to be below requirements frequently. That is of course not the case for other nutrients, whose needs are set at a safe distance above requirements. Since the fear of protein is responsible for the tight margin between protein accretion and recommended intakes, it is the fear of protein that is ultimately responsible for the frequent occurrence of inadequate protein intakes. As will be shown, the fear of protein explains also why the protein content of human milk fortifiers has been kept at a low level for many years. With the high variability in the protein content of expressed milk ( fig. 1 ), there has been concern that protein intakes would be too high if and when the protein content of the human milk was high. This is the reason why the protein content of powder fortifiers was kept at g of protein added per 100 ml of milk. The data in figure 1 also illustrate that with the addition of g protein per 100 ml, total protein concentration only occasionally reaches 2.6 g/100 ml and never reaches 2.8 g/100 ml, the level necessary to meet protein needs of infants. 124Ziegler

5 True protein (g/dl) Age of infants (days) Fig. 1. Protein concentration of milk expressed by mothers of premature infants. It hardly needs mentioning that growth failure is strongly associated with impaired neurodevelopment and the neonatologist must constantly be mindful that growth retardation is likely to have a negative impact on neurodevelopment. The association has been well documented by the seminal study of Ehrenkranz et al. [7] that involved infants born in The study demonstrated a strong association between growth from regained birth weight to hospital discharge with scores assessing intellectual achievement at months. The association between growth and neurodevelopmental outcome was very strongly positive and the presence of growth failure was strongly associated with impairment of neurodevelopment. It needs to be mentioned that growth rates in the two highest quintiles, by exceeding fetal growth rates, met the criteria for catch-up growth. The lowest quintile of weight gain, which included most infants who were ill and/or had complications, showed the worst neurodevelopmental outcomes. Illness is known to lead to low nutrient intakes [8] and this is the presumed mechanism by which neurodevelopmental outcomes were determined, although a direct effect of complications such as necrotizing enterocolitis cannot be excluded. The study by Franz et al. [9] involved infants of very low birth weight born in 2005 who were managed nutritionally in a different (improved) manner in the early days and weeks of life than the infants studied by Ehrenkranz et al. [7]. Yet the infants studied by Franz et al. [9] also showed a strong association between growth before hospital discharge and cognition at Protein Deficiency in Premature Infants 125

6 5 years. It cannot be emphasized enough that in premature infants the prevention of growth failure is of the utmost importance. What can be done to prevent growth failure? In the absence of systematic data linking protein intakes to growth, all we can do is provide a listing of known situations where protein intakes often fall short of required intakes. By paying attention to protein intakes, the neonatologist should be able to mitigate the deleterious effects of protein deficiency. The situations where inadequate protein intake can occur are listed here in chronological order, i.e. in the order in which they may occur in an infant s life. The relative impact of each of the shortfalls depends mainly on the severity of the shortfall and the duration of its presence. During the phase of parenteral nutrition, a consensus seems to have emerged that amino acids should best be started at 3.5 g/kg per day soon after birth and increased to 4.0 g/kg per day. Yet, it is not uncommon to see delays in the initiation of parenteral nutrition and the use of parenteral amino acids in less than the consensus amount of g/kg per day. Inadequate protein intakes during the early days and weeks of life inevitably create shortfalls, the size of which depends on the specifics of the practice and its length and, importantly, on the concurrent use of enteral nutrition. It is, therefore, not possible to estimate the contribution of inadequate parenteral nutrition to the overall protein shortfall. During the transition phase, enteral nutrition gradually replaces parenteral nutrition. Because of the perceived need to keep the use of central lines as short as possible, parenteral nutrition is often phased out more rapidly than enteral feedings are increased. The resulting temporary shortage of overall intakes of energy and protein can be sizable [10]. The nutrient shortfall often leads to a slowing or cessation of growth. Although this inadequate protein intake occurs widely during the transition phase, there are neither data available concerning the size of the shortfall nor on its contribution to the overall shortfall. The obvious remedy is to extend the duration of parenteral nutrition and/or to increase the nutrient content of parenteral solutions. During the final growth or enteral nutrition phase, enteral nutrition is the sole source of nutrients. It is the longest of the phases and the impact of shortfalls is, therefore, likely to be large. The composition of human milk is, of course, never exactly known unless it is measured, but neither is the exact volume of milk or formula consumed by an infant. Feedings are ordered in precise volumes, but feedings are held or diminished frequently for a variety of reasons, and regurgitation is a frequent occurrence. For these reasons, precise feeding volumes that are actually received by the infant are seldom known. There are no studies that have attempted to record actual feed intakes as opposed to intended intakes. So the neonatologist is likely to assume feed volumes that are higher than true feed volumes received. 126Ziegler

7 Major shortfalls of protein intakes occur during the feeding of fortified human milk, regardless of the uncertainties just mentioned. As shown, the protein content of expressed human milk is highly variable ( fig. 1 ). With fortification (powder fortifier), the protein content reaches 1.6 g/100 ml occasionally, but most of the time is well below that level. A protein concentration of 2.8 g/100 ml, which would be necessary to provide a protein intake of at least 4 g/kg per day, is never reached with the addition of g of protein per 100 ml milk, the amount provided by powder fortifiers. As mentioned above, it is the fear of protein that has kept fortifier protein content at this inadequate level to allay the concerns on the part of neonatologists that should the protein content of milk be high, unduly high amounts of protein could be delivered. The newer liquid fortifiers deliver greater amounts of protein ( g/100 ml of milk) and protein intakes are, therefore, adequate most of the time. It may be expected that with the use of liquid fortifiers there will be a decrease in the extent of growth failure. Conclusion Protein needs of premature infants are difficult to meet because, for historical reasons, intakes of protein are kept close to requirements. Growth failure occurs widely among premature infants and provides evidence of the occurrence of inadequate intakes of protein. Shortfalls of protein intakes occur in every phase of premature nutrition, but their relative importance is difficult to assess. Because growth failure is associated with impaired neurodevelopment, efforts must be made to prevent protein deficiency wherever it occurs. Disclosure Statement The author declares no conflict of interest. References 1 Poindexter B: Approaches to growth faltering; in Koletzko B, Poindexter B, Uauy R (eds): Nutritional Care of Preterm Infants. World Rev Nutr Diet. Basel, Karger, 2014, vol 110, pp Fenton TR, Nasser R, Eliasziw M, et al: Validating the weight gain of preterm infants between the reference growth curve of the fetus and the term infant. BMC Pediatr 2013; 13: Ziegler EE, O Donnell AM, Nelson SE, Fomon SJ: Body composition of the reference fetus. Growth 1976; 40: Ziegler EE: Meeting the nutritional needs of the low-birth-weight infant. Ann Nutr Metab 2011; 58(suppl 1):8 18. Protein Deficiency in Premature Infants 127

8 5 Forbes G: Nutritional adequacy of human breast milk for prematurely born infants; in Lebenthal E (ed): Gastroenterology and Nutrition in Infancy. New York, Raven, 1989, pp Goldman HI, Goldman JS, Kaufman I, Liebman OB: Late effects of early dietary protein intake on low-birth-weight infants. J Pediatr 1974; 85: Ehrenkranz RA, Dusick AM, Vohr BR, et al: Growth in the neonatal intensive care unit influences neurodevelopmental and growth outcomes of extremely low birth weight infants. Pediatrics 2006; 117: Ehrenkranz RA, Das A, Wrage LA, et al: Early nutrition mediates the influence of severity of illness on extremely LBW infants. Pediatr Res 2011; 69: Franz AR, Pohlandt F, Bode H, et al: Intrauterine, early neonatal and postdischarge growth and neurodevelopmental outcome at 5.4 years in extremely preterm infants after intensive neonatal nutritional support. Pediatrics 2009; 123:e Miller M, Vaidya R, Rastogi D, et al: From parenteral to enteral nutrition: a nutritionbased approach for evaluating postnatal growth failure in preterm infants. JPEN J Parenter Enteral Nutr 2014; 38: Ziegler